mTORC1 controls fasting-induced ketogenesis and its modulation by ageing

Area of Science:

• Cellular biology
• Metabolic regulation
• Physiology

Background:

• The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth based on nutrient availability.
• While mTORC1's cellular functions are known, its in vivo role in liver physiology, particularly during fasting, is less understood.
• The liver's role in maintaining homeostasis includes producing ketone bodies for energy during fasting.

Purpose of the Study:

• To investigate the role of mTORC1 in regulating hepatic ketogenesis in response to fasting.
• To elucidate the molecular mechanisms by which mTORC1 influences ketone body production.
• To explore the connection between mTORC1 signaling, aging, and liver function.

Main Methods:

• Utilized mouse models with liver-specific genetic manipulation of mTORC1 components (TSC1, raptor).
• Assessed liver size, ketone body production, and ketogenic gene expression in fasted and fed states.
• Investigated the interaction between mTORC1, PPARα, and NCoR1 in regulating ketogenesis.
• Examined mTORC1 signaling and ketogenesis in aged mice.

Main Results:

• Loss of TSC1 (mTORC1 inhibitor) caused fasting-resistant liver growth and impaired ketogenesis.
• Loss of raptor (mTORC1 component) had opposite effects, enhancing ketogenesis.
• mTORC1 inhibition was essential for fasting-induced PPARα activation and ketogenic gene expression.
• Suppression of NCoR1 reactivated ketogenesis in hyperactive mTORC1 conditions.
• Aged livers showed impaired ketogenesis linked to increased mTORC1 signaling.
• mTORC1 inhibition prevented age-related defects in ketogenesis.

Conclusions:

• mTORC1 is a critical regulator of hepatic ketogenesis and PPARα activity.
• mTORC1 signaling plays a significant role in the age-related decline of liver function.
• Targeting mTORC1 may offer therapeutic strategies for metabolic dysfunction in aging livers.